total parenteral nutrition vs enteral nutrition

Author's Final Version of: Simpson F and Doig GS. Parenteral vs. enteral nutrition in the critically ill patient:A meta-analysis of trials using the intention to treat principle. Intensive Care Med 2005;31(1):12-23.

The original publication is available at: http://www.springerlink.com/openurl.asp?genre=article&id=doi:10.1007/s00134-004-2511-2

© 2005. Duplication for personal or educational use is acceptable.

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Parenteral vs. enteral nutrition in the critically ill patient:

A meta-analysis of trials using the intention to treat principle.

Fiona Simpson1 and Gordon Stuart Doig2

1Department of Nutrition and 2Intensive Therapy Unit, Royal North Shore Hospital,

Sydney, Australia.

Corresponding Author:

Dr. Gordon S. Doig

Senior Lecturer in Intensive Care

Northern Clinical School,

University of Sydney

Mailing Address:

Royal North Shore Hospital

Intensive Therapy Unit

Pacific Highway

St. Leonards, NSW

Australia 2065

e-mail: [email protected]

phone: 612 9926 8656

fax: 612 9439 8418

Word Count: (Abstract: 249 words, Text body: 3,996).




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Structured AbstractBackground: Controversy surrounds the use of parenteral nutrition in critical illness.

Previous overviews used composite scales to identify high-quality trials, which may

mask important differences in true methodological quality. Using a component-based

approach, this meta-analysis investigates the effect of trial quality on overall

conclusions reached when standard EN is compared to standard PN in critically ill

patients.

Methods: An extensive literature search was undertaken to identify all eligible trials.

Measurements and results: 465 papers were retrieved. Eleven trials qualified for

inclusion.

Nine trials presented complete follow-up, allowing the conduct of an intention

to treat analysis (ITT). Aggregation revealed a mortality benefit in favour of PN

(OR=0.51, 95% CI 0.27 to 0.97, p=0.04), with no heterogeneity.

A priori specified subgroup analysis demonstrated the presence of a

potentially important treatment-subgroup interaction between studies of PN vs. early

EN compared to PN vs. late EN (OR=1.07 PN vs. early EN, OR=0.29 PN vs delayed

EN, p=0.055, test of treatment-subgroup interaction).

Six trials with complete follow-up reported infectious complications. Infectious

complications were increased with PN use (OR=1.66, 95% CI 1.09 to 2.51; p=0.02).

The I2 measure of heterogeneity was 37.7%.

Conclusions: ITT trials demonstrated reduced mortality associated with PN use. A

priori subgroup analysis attributed this reduction to trials comparing PN to delayed

EN. Despite an association with increased infectious complications, a Grade B+

evidence-based recommendation (Level II trials, no heterogeneity) can be generated

for PN use in patients in whom EN cannot be initiated within 24 hours of ICU

admission or injury.

Word Count = 249

Descriptor: 18. Nutrition

Key Words (up to 6): Enteral Nutrition, Parenteral Nutrition, Meta-analysis,

randomised controlled trials, Critical illness, critical appraisal




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Introduction

Parenteral nutrition (PN) has been in common use since the 1960’s [1], and is

accepted as the standard of care for patients with chronic non-functioning

gastrointestinal tracts [2,3]. The appropriate use of PN in the intensive care unit (ICU)

however, is somewhat more controversial [4,5].

A recent survey revealed that, depending on country of admission, 19 to 71% of

patients received PN as their sole source of nutritional support at some time during

their ICU stay [6]. The promotion of high-quality evidence has been shown to result in

a more consistent approach to the provision of nutritional support, which led to

improved patient outcomes [7].

Although the results obtained from well conducted Level I studies often disagree

with the findings of meta-analyses based on Level II trials [8], rigorously conducted

systematic reviews can be used to support clinical decision making [9]. The strength

of the conclusions reached by a systematic review however, are intimately related to

the quality of the individual trials included in it [10]. The importance of considering

individual trial quality can be illustrated by contrasting the results of two recent meta-

analyses.

The Cochrane Injuries Group Albumin Reviewers (CIGAR) meta-analysis

reported treatment with human serum albumin increased the risk of death compared

with either crystalloids or no treatment [11]. The CIGAR paper included numerous

pseudo-randomised trials, which are known to be subject to allocation bias [12]. A

subsequent meta-analysis, which specifically addressed individual components of

trial methodological quality, found that when only high-quality trials were considered,

there was no significant effect of albumin use on overall mortality [13]. The inclusion




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of trials of low methodological quality is known to have a substantial impact on the

conclusions reached by meta-analyses [14].

Previous systematic reviews of nutritional support interventions [15,16,17,18],

have identified high-quality studies using composite methodological quality scales

[19], which combine different dimensions of trial quality into an overall summary

score. Most composite scales are known to have used weak methodology when

selecting items for inclusion and ranking them for relative importance [20].

The composite scale selected to reflect overall trial quality can dramatically

influence the conclusions of a meta-analysis [21]. Because composite scales may

mask important differences in true methodological quality, the use of a 'component

approach' has been recommended [22,10]. A component approach assesses key

methodological dimensions individually, without the calculation of a summary score

[14].

The purpose of this meta-analysis was to use a component approach to

investigate the effect of methodological quality on the overall conclusions reached

when trials comparing the use of standard PN to standard EN in critically ill patients

were aggregated.

Materials and Methods

Literature search

Medline (www.PubMed.org ) and EMBASE (www.Ovid.com) were cross-

searched using sensitive (broad) search statements [23] customised to each engine

to detect all controlled trials, overviews and evidence-based guidelines of primary

feeding interventions. Reference lists of overviews and evidence-based guidelines

were hand searched. Experts and Industry representatives were contacted in order to

http://www.pubmed.org/

http://www.ovid.com/




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ensure trials were not missed. The final closeout date for the search process was

April 30, 2003.

Study selection

All controlled trials comparing primary feeding interventions, published in the

English language [14,24], were reviewed. Only truly randomised trials comparing

standard EN to standard PN and reporting clinically meaningful outcomes were

eligible. Standard EN and PN solutions were defined as any solution not

supplemented with additional glutamine, arginine or other immune enhancing

ingredients. PN was defined as an intravenous solution containing protein and a

source of nonprotein energy with or without lipids [18].

Because previous overviews detected heterogeneity between critically ill and

non-critically ill patient populations [18], an explicit, objective definition of a critically ill

patient population was applied (Table 1)[25]. Trials conducted in non-critically ill

patient populations were not considered for inclusion.

True Methodological Quality

Methodological quality was based on the reporting of three key methodological

components in the published manuscript: 1) presentation of an intention to treat (ITT)

analysis; 2) maintenance of allocation concealment during randomisation and; 3)

appropriate use of blinding (eg. participants, investigators, outcome adjudicators etc.)

[14,22].

To investigate the effect of trial quality on overall conclusions, a series of

meta-analyses were planned. The initial meta-analysis considered trials that

addressed all three dimensions of quality, followed by meta-analyses based on each

component individually.




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To address the impact of incomplete follow-up, a sensitivity analysis was

undertaken. The primary meta-analysis was conducted on all trials presenting

complete follow-up. Since some degree of random loss to follow-up may occur,

complete follow-up was defined as full reporting on at least 95% of all patients. The

sensitivity analysis was conducted including trials reporting loss to follow-up by study

arm, where the total loss did not exceed 10% of all patients. The conservative

assumption that the lost patient encountered an undesirable outcome was made.

The presence of excessive loss to follow-up, defined as loss to follow-up on

more than 10% of patients, was considered a major methodological flaw [26,27].

Trials with excessive loss to follow-up were not eligible for consideration [28].

Any differences in interpretation were resolved by discussion.

A priori defined subgroup analysis

A treatment-subgroup interaction was investigated for trials comparing early

EN initiation to PN and trials comparing late EN initiation to PN. Early EN was

defined as feeding within 24 hours of ICU admission or initial injury [7].

Outcomes assessed

A clinically meaningful outcome was defined as a direct measure of how a

patient feels, functions or survives [29]. Any trial explicitly reporting clinically

meaningful outcomes (eg. a validated quality of life instrument, duration of survival,

quality adjusted survival or landmark mortality) was considered for inclusion. Trials

reporting only unvalidated surrogate outcomes were not eligible for inclusion [30].

Previous reviewers have suggested that infectious complications (ICs) may be

clinically important [15]. The presence of an IC was defined by positive culture

results. Since it is generally difficult to determine when one infection has resolved

and a second, independent, infection has begun, the proportion of individual patients




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with positive cultures was abstracted in preference to the total number of positive

cultures [31].

Statistics

Meta-analyses were conducted with a fixed effects model [32] using the odds

ratio metric [33]. The presence of heterogeneity was assessed using the chi-square

statistic [32] and the I2 measure [34]. The presence of a priori hypothesised subgroup

differences were investigated using a formal test of treatment-subgroup interaction

[35].

Primary analysis was conducted using Revman (RevMan Version 4.2 for

Windows. Oxford, England: The Cochrane Collaboration®, 2003). Formal tests of

treatment-subgroup interactions were conducted using PC SAS proc logist (PC

SAS® version 6.12, SAS Institute Inc., SAS Circle, PO Box 8000,Cary, NC, 27512-

8000, U.S.A.). Primary stratification by study was maintained using dummy variable

coding.

A p-value less than 0.05 indicated statistical significance, while a p-value

greater than 0.05 but less than 0.10 indicated a trend towards statistical significance.

A p-value less than 0.10 was used to indicate the presence of potentially important

heterogeneity or subgroup-treatment interactions.

Results

Literature search and Study selection

Cross-searching Medline (from 1966) and EMBASE (from 1980) revealed

2,287 unique abstracts. Independent review of all abstracts resulted in the retrieval of

465 papers. Figure 1 presents the results of the study selection process using the

flow-diagram recommended by the Quality of Reporting of Meta-analyses

(QUOROM) conference participants [36]. No non-English language publications were




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identified on this topic. Twenty-two trials were found to compare the effects of EN to

PN on clinically meaningful outcomes in a critically ill patient population.

Five of the 22 publications were based on subgroups of patients that were

reported in a subsequent larger published trial [37,38,39,40,41] and thus did not

qualify for inclusion as individual trials.

Three of the remaining 17 trials compared immune enhanced EN and/or PN

[42,43,44] and one trial was pseudo-randomised, using an alternating date of

admission allocation sequence [45].

Of the remaining 13 trials, one failed to report outcomes on 21% of all

randomised patients [46] and a second failed to report outcomes on 12% of all

randomised patients [47]. Neither of these trials reported loss to follow-up by study

arm.

Nine studies qualified for consideration in the primary analysis with two

additional studies qualifying for the sensitivity analysis. Eight studies presented

100% follow-up [48,49,50,51,52,53,54,55] and one study reported complete follow-up

(outcomes reported on 95% of all randomised patients) [56]. One paper reported

outcomes on 94.3% of all randomised patients [57], and one reported outcomes on

91.5% of all randomised patients [58]. Loss to follow-up in all three trials was

reported by study arm.

Table 2 presents further details describing the study population, criteria used

to identify the critically ill patient population and nutritional support goals for each of

the eleven included trials.




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True Methodological Quality

None of the eleven trials explicitly reported the maintenance of allocation

concealment and only one reported the use of blinding [48]. Nine of the eleven

presented sufficient follow-up to allow the conduct of an ITT analysis.

Reporting of infectious complications

Six of the trials with complete follow-up reported positive cultures. Three trials

reported the number of individual patients with positive cultures [48,53,56] and three

reported the total number of positive cultures but not the number of patients with

positive cultures [49,55,52].

The types of ICs reported by each trial are presented in Table 3.

Publication bias

Formal assessment of the funnel plot did not yield any evidence of a

publication bias.

Primary analysis: mortality

Landmark mortality was the only clinically meaningful outcome reported in all

trials. When the nine trials presenting ITT results were aggregated, a statistically

significant mortality benefit was evident for the use of PN (OR=0.51, 95% CI 0.27 to

0.97, p=0.04, figure 2). The chi-square test for heterogeneity was non-significant

(p=0.50) and the I2 measure was zero.

Primary analysis: infectious complications

When the six trials reporting positive culture results were aggregated, there

was a significant increase in ICs with PN use (OR=1.66, 95% CI 1.09 to 2.51;

p=0.02, figure 3). The chi-square test for heterogeneity was non-significant (p=0.16).

The I2 measure of heterogeneity was 37.7%.




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A-priori subgroup analysis

Timing of feeding and effect on clinically meaningful outcomes

Six of the nine trials commenced enteral feeding within 24 hours of intensive

care admission or injury [48,49,53,50,51,55]. In all cases, early EN was achieved via

transpyloric or jejunal feeding tubes.

Three trials did not meet the definition of early enteral feeding (< 24 hrs). Two

began EN within 48 hours of ICU admission or injury [56,54] while the third trial

enrolled patients when there was an "actual or anticipated inadequate oral intake for

longer than seven days" [52].

Maintaining stratification by study, there was a potentially important (OR=1.07

PN vs. early EN, OR=0.29 PN vs delayed EN, p=0.055) difference in the magnitude

of the treatment effect for PN vs. early EN compared to PN vs. late EN (i.e. a

treatment-subgroup interaction).

When the use of PN was compared to the provision of early EN, there was no

significant effect on mortality (OR=1.07, 95% CI 0.39 to 2.95, p=0.89, figure 4). The

chi-square test for statistical heterogeneity was non-significant (p=0.75) and the I2

measure was zero.

Compared to the provision of delayed EN, there was a statistically significant

mortality benefit in favour of the use of PN (OR=0.29, 95% CI 0.12 to 0.70, p=0.006).

There was no evidence of statistical heterogeneity (p=0.60) and I2 was zero.

Details regarding the timing of the onset of feeding for each trial are presented

in Table 2.

Timing of feeding and effect on infectious complications

Of the six trials reporting ICs, four trials compared early EN to PN. When

aggregated, the use of PN approached a statistical trend towards more ICs




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compared to early EN (OR=1.47, 95% CI 0.90 to 2.38; p=0.12). Potentially important

heterogeneity was present (p=0.07), and the I2 measure was 56.9%.

Only two trials comparing late EN to PN reported ICs [52,56]. Due to the small

number of trials, a meta-analysis could not be conducted. Individually, neither trial

reported a significant difference in ICs.

Sensitivity Analysis

Two additional trials qualified for consideration in the sensitivity analysis

[57,58]. Based on aggregation of all eleven trials, the statistically significant mortality

benefit remained in favour of PN use (OR=0.56, 95% CI 0.33 to 0.93, p=0.03, figure

4). The chi-square test for heterogeneity was non-significant (p=0.51) and the I2 was

zero.

Both additional trials compared PN with late EN. In one study, patients were

required to have persistent coma (GCS < 9) for at least 24 hours prior to

randomisation [58] and in the second, patients were enrolled within 4 to 6 days of

sepsis or surgery [57].

Considering these additional trials in the analysis of PN compared to late EN,

the significant mortality benefit of PN remained (OR=0.44, 95% CI 0.24 to 0.81,

p=0.008, figure 4). The test for statistical heterogeneity was non-significant (p=0.35)

and the I2 measure was 10.0%.

Discussion

We used a component approach to assess the effect of methodological quality

on the results obtained when trials comparing the use of standard PN to standard EN

were aggregated. Since the extensive search did not detect any non-English

language publications, it is unlikely a significant Language Bias exists [14] on this

topic.




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When ITT trials were considered, a statistically significant mortality benefit was

evident in favour of PN (OR=0.51). Based on an a priori specified subgroup analysis,

this overall benefit was attributable to trials that compared the use of PN to delayed

EN (OR=0.29). Although ICs were significantly increased (OR=1.66), given the

evidence of a mortality benefit, the clinical importance of these infectious

complications should be questioned.

Clinically meaningful outcomes

Although the results of the current overview may appear novel, they are

robust. When two additional trials were considered in the a priori defined sensitivity

analysis, the statistically significant mortality benefit in favour of PN remained

(OR=0.56) and, as suggested during the review process, when a more conservative

random effects model was applied to the ITT trials, the benefit in favour of PN also

remained (OR=0.49, 95%CI 0.25 to 0.98, p=0.04). Finally, although a previous

review conducted on this topic reported non-significant results (OR=0.91, 95% CI

0.51 to 1.62), which resulted in a recommendation for the use of EN in preference to

PN, it did not rule out the possibility of a mortality benefit in favour of PN [15]. Indeed,

the point estimate of mortality benefit obtained in this current meta-analysis

(OR=0.51) falls within the 95% confidence interval obtained in the previous review

[15], which included numerous studies of questionable methodological quality

[45,46,47].

The purpose of using a component approach to appraise trials was to

investigate the impact of bias on the overall conclusions [14]. Nine of eleven trials

considered in this meta-analysis presented complete (> 95%) reporting and follow-

up, which enables the conduct of an ITT analysis. An ITT analysis is known to

provide the most conservative estimate of treatment effect [59] and protects against




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attrition bias, which results from nonrandom loss to follow-up [27]. Recent editorials

reveal a strong prejudice against the use of PN in critically ill patients [5,60]. It is

possible that the current findings are due to the exclusion of low-quality trials that

overestimated the benefit of EN due to an inherent prejudice against PN use.

The results obtained from this current overview are also consistent with the

evidence-based recommendations (EBRs) made in a recent cluster randomised trial

(cRCT) evaluating the impact of evidence-based ICU feeding guidelines [7]. The

guideline evaluated in this cRCT included a strong EBR for early feeding (within 24

hours of ICU admission) with preference to the enteral route. If it was anticipated that

enteral feeding could not be initiated within 24 hours of ICU admission, the early use

of PN was recommended. Our a priori specified subgroup analysis compared the

effect of PN in trials that initiated early EN (<24hrs) to the effect of PN in trials where

EN was delayed. While there was no benefit from the use of PN when EN was

initiated early, there was a statistically significant benefit from the use of PN in trials

where EN was delayed (OR=0.29, p=0.006). The statistically significant benefit in this

subgroup remained when additional trials were considered in the sensitivity analysis.

Infectious complications

The current overview documented a statistically significant increase in ICs

associated with PN use (OR=1.66). A previous review also documented an increase

in ICs (OR=2.51, 95% CI 1.66 to 3.79, p<0.0001) [15]. Although the point estimate for

increased ICs obtained from the current overview (OR=1.66) is more conservative, it

is contained within the 95% CI generated by the previous review, which included

trials of questionable methodological quality [46,47].

It is known that estimates of treatment effect decrease when more rigorous

definitions of clinical infections are employed [61]. Previous reviews pooled




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suspected infections (eg. fever of unknown origin) with positive culture results to

obtain ‘total infectious complications'. Considering that no trials of PN vs. EN

adjudicated suspected infections using an objective, blinded, repeatable process, it is

likely that this outcome is highly susceptible to bias. We employed a more objective

definition of infection, based on positive culture results, and obtained a marginally

lower estimate of IC rates due to PN use.

A comprehensive review of the clinical importance of ICU-based infections

found that the nature of the organism, the site of infection and the interaction

between organism and site all had a significant impact on outcome [62]. Based on

this finding, an approach to classifying and combining ICU infections that accurately

reflects the contribution that the infecting organism makes to patient outcome was

proposed [62]. Due to incomplete reporting, it was not possible to classify and

combine infections based on risk of outcome (eg. severe infection, moderate

infection, sub-clinical infection). Although the chi-square test for statistical

heterogeneity was non-significant (p=0.16), the I2 measure of heterogeneity was

37.7%, suggesting it may not be appropriate to pool all types of infections.

Statistical heterogeneity is said to be present in a meta-analysis when the

differences in outcomes between studies is greater than expected by chance alone

[34]. In the presence of unexplained heterogeneity, pooling of study results may not

be appropriate, even with a random effects model [32]. Although a chi-square test is

commonly used to detect the presence of heterogeneity, this test has very poor

power when the number of included studies is low [63]. The I2 statistic is an accepted

measure of heterogeneity that does not depend on the number of included studies for

interpretation [34].




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Interpretation of the I2 measure reveals that 37.7% of the total variability in ICs

was attributable to true differences between studies (heterogeneity) rather than

random variability (sampling error). Although there are no clear guidelines as to what

constitutes an unacceptable level of heterogeneity as measured by I2, a value of 20%

reflects the presence of moderate heterogeneity [34].

Irregardless of whether the clinician interprets information obtained from all

trials (OR=1.66), from trials reporting the number of patients with infections

(OR=1.88) or from trials reporting only the total number of infections (OR=1.46)

(Figure 3), the ORs, and thus the estimate of increased ICs attributable to PN, are

remarkably similar. Indeed, as suggested during the review process, if the incidence

of infection is considered, which accounts for patient-time at risk, the OR does not

change (OR=1.51). Irregardless of the approach used to aggregate infections, the

clinician should be aware that the use of PN was associated with an increase in

infectious complications. Because all infections do not lead to similar outcomes and

inconsistent definitions of infections were used in each trial, the clinical importance of

this finding is open to interpretation.

True methodological quality:

Although previous reviewers have based their assessment of methodological

quality on published manuscripts [15,16,17,25,64], it has been suggested that direct

communication with the authors of contributing trials could improve our

understanding of methodological quality. Due to resource and logistical constraints,

we were unable to communicate directly with the authors of the papers reviewed in

this meta-analysis. Although the current state of knowledge regarding the importance

of methodological quality is based on assessments of published manuscripts, not




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direct communication with authors [10,12,14,22,36], we believe this is an area that

merits further research.

The two main areas of methodological quality that were consistently found to

be deficient in the manuscripts reviewed for this meta-analysis were the appropriate

use of blinding and explicit reporting of allocation concealment.

Blinding

Since the appropriate use of blinding can reduce overoptimistic estimates of

treatment effects by up to 26% [10], many novel and innovative processes have been

developed for blinding complex intensive care interventions [65,66]. Regardless of

the complexity of the intervention, if a subjective outcome (eg. ventilator associated

pneumonia, suspected infection etc.) is important, it is always possible to blind

outcome adjudicators. Because it may be important to understand whether patients,

health care providers, researchers, outcome adjudicators, data collectors and even

the data analysts were blinded, use of the term 'double blinded' is discouraged in

preference to an explicit list of exactly who was blinded [67].

Allocation concealment

Trials with inadequate or unclear reporting of allocation concealment are

known to produce up to 40% larger estimates of treatment effects [10,12]. Allocation

concealment refers to a process used to randomise participants so that patients,

clinicians and researchers cannot predict or influence which participants are

assigned to a given intervention (Definition of allocation concealment contained on

the Consolidated Standards of Reporting Trials web site, http://www.consort-

statement.org/allocationconcealment.htm, accessed 21 June 2004). A single

sentence describing the use of 'sealed, opaque, sequentially numbered envelopes',

http://www.consort-statement.org/allocationconcealment.htm

http://www.consort-statement.org/allocationconcealment.htm




17

or a 'central call-in randomisation centre' is sufficient to ensure the reader that

allocation concealment was maintained [12].

Summary

The inclusion of trials of low methodological quality is known to have a

substantial impact on the results and conclusions obtained from meta-analyses [14].

Based on the results of the nine trials presenting complete follow-up, meta-

analysis revealed a significant mortality benefit in favour of the use of PN. A priori

specified subgroup analysis demonstrated the benefit from PN use was greatest in

trials where EN was delayed (> 24hrs). Although we also documented an increase in

ICs with PN use, because we were unable to separate sub-clinical infections from

serious infections, in the face of improved mortality, the clinical importance of these

ICs could not be established.

The overall findings of this meta-analysis would not lead us to recommend the

use of PN in patients in whom EN could be initiated within 24 hours of ICU admission

or injury. In consideration of the overall results, including the increase in ICs, a Grade

B+ evidence-based recommendation [68] could be generated for the use of PN in

patients in whom EN could not be initiated within 24 hours of ICU admission or injury.

This Grade B+ EBR, where the 'B' indicates the recommendation is based on Level II

evidence and the '+' indicates there is no heterogeneity between trials ('Evidence-

based Recommendations section of the Evidence-based Decision Making in Critical

Care web site', http://www.EvidenceBased.net, accessed 16 June 2004), is

consistent with the explicit recommendation made for PN use in a recent cluster

randomised trial of evidence-based ICU feeding guidelines that resulted in an overall

10% reduction in mortality [7].

http://www.evidencebased.net/




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It is important to recognise that the clinical trials included in this meta-analysis

constitute Level II evidence [68]. Because meta-analyses based on Level II evidence

often disagree with the findings of subsequent, well-conducted Level I trials [8], we

strongly recommend the conduct of a Level I study addressing the use of standard

PN in patients in whom standard EN cannot be started for at least 24 hours after ICU

admission or initial injury. This study should be adequately powered to detect a

difference in a clinically meaningful outcome, should employ a blinded assessment of

clinically important infections and should embrace all major aspects of study design

that are known to reduce bias. In addition, the conduct of such a trial would present

the ideal opportunity to conduct a full economic analysis of the use of PN compared

to EN, expressed as costs per life saved [69].

Acknowledgments

This work was supported in part by grants from the Australian and New Zealand

Intensive Care Foundation and the NorthCare Foundation.

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Table 1: Identification of papers conducted in a critically ill patient population

A study was determined to have been conducted in a critically ill patientpopulation if the manuscript reported:

1) the patients were recruited in an intensive care unit (ICU) or;2) the inclusion criteria described were such that the patients would

normally be cared for in an ICU (eg. all patients were receivinginvasive mechanical ventilatory support) or;

3) the patients were suffering from a condition that usually requirescare in an ICU (eg. severe thermal burns of > 40-50% TBSA, multitrauma that required urgent laparotomy) or;

4) the patients had an average ICU length of stay greater than twodays or;

5) a majority of the patients received a therapy that is delivered in theICU (eg. invasive mechanical ventilation) or;

6) a severity of illness score was reported that was commensuratewith the patients being critically ill.

Table 2: Identification of papers conducted in a critically ill patient population

The original publication is available at: http://www.springerlink.com/openurl.asp?genre=article&id=doi:10.1007/s00134-004-2511-2© 2005. Duplication for personal or educational use is acceptable.

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Study Patient population Criteria identifyingcritical illness

Nutritional supportgoals (per day)*

Time from ICU admission / injury to onset ofnutritional support

Kudsk1994

Abdominal trauma patients requiring alaparotomy.

Mean ICU stay ofapproximately 5 days.

30-35 kcal/kg and1.5-2.0g protein/kg EN & PN were started within 8 hours of surgery.

Dunham1994

Patients admitted to the ICU for blunttrauma.

Expected to requiremechanical ventilation for 48hours after randomisation.

Harris-Benedict witha 1.3 X stress factor

Patients were evaluated approximately 18 hoursafter ICU admission. If patient was not able to berandomised (and fed) 30 hours after ICUadmission, they did not qualify for study entry.

Rapp1983

Penetrating missile wounds or blunthead trauma.

Study admission requiredintracranial haematoma withfocal neurological deficitsand/or loss of consciousness

ENR: 685 kcal and4g nitrogenPNR: 1750 kcal and10.2g nitrogen

EN was begun when bowel sounds present. PNwas begun within 48 hours of surgery.

Adams1986

Trauma patients undergoing anemergent laparotomy.

Mean ICU stay between 10to 13 days.

Harris-Benedict witha 1.68 or 2.0 X stressfactor.

EN & PN were begun on the first post-op day.

Borzotta1994 Head trauma patients. GCS ≤ 8 for at least 24

hours.Harris-Benedict witha 1.5 X stress factor

EN was begun an average of 2.4 days postinjury. PN was begun an average of 1.8 dayspost injury.

Kalfarentzos1997 Severe acute pancreatitis. All patients required ICU stay

longer than 72 hours.30-35 kcal/kg and1.5-2.0g protein/kg

EN was begun within 48 hrs of ICU admission.PN was likely begun immediately afterrandomisation. Not specifically stated.

Cerra1988

Hypermetabolic patients, enrolledwithin 4 to 6 days after the conduct ofsurgery and onset of sepsis.

Patients enrolled and studyconducted in an ICU.

30 kcal/kg and 1.5gprotein/kg

Not specifically stated. Patients were enrolled 4to 6 days after the onset of sepsis.

Woodcock2001

Actual or anticipated inadequate oralnutritional intake for 7 days or morewith a reasonable doubt as to theadequacy of intestinal function.

Only patients randomised inICU were included in themeta-analysis. 59% of allpatients were randomised inthe ICU.

30 kcal non-proteinenergy and 9gnitrogen

"Actual or anticipated inadequate oral intake forlonger than seven days." Average time notreported. Very unlikely to be less than 24 hoursfrom ICU admission.

Rayes2002

Adult patients undergoing electivelaparotomy and resection of the liver,stomach, colon or pancreas.

Mean ICU stay between 2and 3 days.

ENR: 1500 kcal and60g proteinPNR: 1800 kcal and70g protein

EN & PN were begun within 24 hrs of surgery.

Reynolds1997

Patients undergoing surgery foroesophageal, gastric or pancreaticcancer.

53 of 67 randomised patients(a majority) had procedureswhich would commonlyrequire ICU admission.

ENR: 1300 kcal and8g nitrogenPNR: 1800 kcal and10g nitrogen

EN & PN were begun 9am first post-op day.

Gianotti1997 Gastric or pancreatic cancer patients. Patients enrolled and study

conducted in an ICU.25 kcal/kg and 0.25 gnitrogen/kg

EN begun 6 hours post surgery. Timing of PNstart not specifically stated.

*Unless indicated, goals were identical in EN and PN groups. If goals were not reported, ENR indicates EN received and PNR indicates PN received.EN: enteral nutrition, PN: parenteral nutrition, ICU: intensive care unit



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Table 3: Infectious complications reported by study

Study Reporting detail Infections reported

Rayes2002

total number ofindividualpatients withinfections

sepsis, peritonitis, wound infections,pneumonia or urinary tract infections(UTI) up to 30 days post hospitaldischarge

Gianotti1997


Abdominal abscess, wound infections,pneumonia, infected pancreatic orbiliary fistula and UTI throughouthospital stay

Kalfarentzos1997


sepsis, pneumonia, UTI and infectednecrosis or intra-abdominal abscess

Reynolds1997

total number ofinfectiouscomplications

intra-abdominal/thoracic abscess,pneumonia or abscess, and central linesepsis within 30days of surgery

Adams1986


wound infections, pneumonia and intra-abdominal infections up to a maximumof 14 days

Woodcock 2001


chest and wound infections, linesepsis, intra-abdominal abscess andsepticemia throughout the entirehospital stay for all patients (not justthose randomised in ICU)



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Figure 1: QUOROM flow-chart illustrating the study selection process

Legend:RCT: Randomised controlled trialN: Number of papersEN: Enteral nutritionPN: Parenteral nutrition

Figure 2: TPN versus EN. Effect on mortality: Primary ITT analysis.

Legend:EN: Enteral nutritionTPN: Total parenteral nutritionOR: Odds ratioN: Total number of patients in the groupn: Number of patients that died in the group

Figure 3: TPN versus EN. Effect on infectious complications. Primary ITTanalysis

Legend:EN: Enteral nutritionTPN: Total parenteral nutritionOR: Odds ratioN: Total number of patients in the groupn: Number of patients with infectious complications (or total number of infectiouscomplications) in the group

Figure 4: TPN versus EN. Effect on mortality: Sensitivity analysis andsubgroup analysis

Legend:EN: Enteral nutritionTPN: Total parenteral nutritionOR: Odds ratioN: Total number of patients in the groupn: Number of patients that died in the group

Figure 1

The original publication is available at: http://www.springerlink.com/openurl.asp?genr

© 2005. Duplication for p

Potentially relevant papers identified andretrieved: (N=465)

RCTs reviewed for more detailed e(N=329)

Potentially appropriate RCTs to befor the meta-analysis: (N=124)

RCTs comparing EN to PN: (N=22

RCTs comparing standard EN withwith minimal loss to follow-up repormeaningful outcomes: (n=11)

Papers excluded, with reasons:• N=136, Not RCTs (Letters, true

observational studies, systematic reviews,narrative reviews, previous meta-analyses).

e=e

valuation:

c

)

sti

RCTs excluded, with Reasons:• N=103, Did not report clinically meaningful

outcomes.• N=43, Not conducted in critically ill patients.• N=27, Not primary nutritional support studies.• N=15, Cross-over trials.• N=12, Evaluated pre-operative interventions.• N=5, Pseudo-randomised.

article&id=doi:10.1007/s00134-004-2511-2

rsonal or educational use is acceptable.

28

onsidered

RCTs excluded from meta-analysis, withreasons:• N=102, Did not provide a primary

comparison of EN to PN.

RCTs comparing EN to PN withdrawn, withreasons:• N=5, Paper based on subgroups of patients

reported in subsequent trials.• N=3, Compared immune enhanced EN or PN.• N=1, Pseudo-randomised.• N=1, Excessive (21%) loss to follow-up.• N=1, Excessive (12%) loss to follow-up.

tandard PNng clinically



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Figure 2

Figure 3



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Figure 4

total parenteral nutrition vs enteral nutrition

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